EP1545709B1 - Präoperative behandlung von brustkrebs - Google Patents

Präoperative behandlung von brustkrebs Download PDF

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Publication number
EP1545709B1
EP1545709B1 EP03750185A EP03750185A EP1545709B1 EP 1545709 B1 EP1545709 B1 EP 1545709B1 EP 03750185 A EP03750185 A EP 03750185A EP 03750185 A EP03750185 A EP 03750185A EP 1545709 B1 EP1545709 B1 EP 1545709B1
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Prior art keywords
administration
combination
patient
diphenyl compound
chemotherapeutic agents
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English (en)
French (fr)
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EP1545709A1 (de
Inventor
Lorne J. Brandes
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University of Manitoba
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University of Manitoba
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the treatment of breast cancer.
  • chemotherapeutic treatments are that of malignant growth (cancer) in humans.
  • the objective of chemotherapy is the total extermination of clonogenic tumor or malignant cells, with minimal damage to the patient.
  • cancer malignant growth
  • Anti-neoplastic agents have the lowest therapeutic indicies of any class of drugs used in humans and hence produce significant and potentially life-threatening toxicities.
  • Certain commonly-used anti-neoplastic agents have unique and acute toxicities for specific tissues.
  • the vinca alkaloids possess significant toxicity for nervous tissues, while adriamycin has specific toxicity for heart tissue and bleomycin has for lung tissue.
  • almost all members of the major categories of anti-neoplastic agents have considerable toxicities for normal cells of gastrointestinal, epidermal and myelopoietic tissues.
  • the dose-limiting consideration for chemical management of cancer in humans is the toxicity that anti-neoplastic agents have for the pluripotent stem cells of myelopoietic tissue. This toxicity arises from the fact that most anticancer drugs function preferentially against proliferating cells but with no significant capacity to discriminate between cycling normal and cycling tumor tissues.
  • T3 tumors are tumors sized >3 and ⁇ 4 cm. T3 tumors may be operable or inoperable depending on where in the breast they are located. For example, they are often inoperable if close to the chest wall, especially in small breasts. T4 tumors are tumors sized >4 cm and generally are inoperable. Inflammatory breast cancer infiltrates the lymphatics of the skin, is usually a diffuse tumor and very high grade in term of malignancy.
  • DPPE N,N-diethyl-2-[4-(phenylmethyl)-phenoxy]ethanamine
  • the diphenyl compound and the chemotherapeutic agents are generally administered by intravenous infusion.
  • a solution of the diphenyl compound is administered to the patient over a desired period of time prior to administration of the chemotherapeutic agents and a solution of the chemotherapeutic agents in combination with the diphenyl compound then is administered for the period of administration of the chemotherapeutic agents.
  • a solution of the diphenyl compound is administered after completion of the administration of the chemotherapeutic agents for a desired period of time to ameliorate side effects from the administration of the chemotherapeutic agents.
  • a diphenyl compound which is a potent antagonist of histamine binding at the intracellular histamine receptor and is administered in an amount sufficient to inhibit the binding of intracellular histamine at the intracellular binding site (H IC ) in normal cells.
  • H IC intracellular binding site
  • Such compounds exhibit a pKi of at least about 5, preferably at least about 5.5.
  • Pharmaceutically-acceptable salts of the diphenyl compounds may be employed.
  • benzene rings may be joined to form a tricyclic ring, in accordance with the structure:
  • the group is a diethylamino group, although other alkylamino groups may be employed, such as dimethylamino, and, in another preferred embodiment, a morpholino group, although other heterocyclic ring groups may be employed, such as piperazino.
  • o and p are usually 0 when Z is an alkylene group and n may be 2. In one particularly preferred embodiment, Z is -CH 2 -, n is 2, o and p are each 0 and is a diethylamino group.
  • This compound namely N,N-diethyl-2-[4-(phenylmethyl)-phenoxy]ethanamine, which may be in the form of the free base or in the form of its hydrochloride or other pharmaceutically-acceptable salt, is abbreviated herein as DPPE.
  • DPPE N,N-diethyl-2-[4-(phenylmethyl)-phenoxy]ethanamine
  • Other substitutents may be provided on the benzene rings in addition to the halogen atoms, for example; an imidazole group.
  • the diphenyl compound employed in the present invention is administered to the patient in any convenient manner, such as by intravenous injection of a solution thereof in an aqueous pharmaceutically-acceptable vehicle.
  • the diphenyl compound is administered to the patient over a period of time before administration of the chemotherapeutic agents.
  • the chemotherapeutic agents employed herein are anthracyclines, preferably doxorubicin and epirubicin; and taxanes, preferably Taxol (Trademark of Bristol-Myers Squibb for paclitaxel) and Taxotere (Trademark of Aventis Pharma for docetaxel).
  • the mixture of chemotherapeutic agents is administered in any manner consistent with their normal manner of administration in conventional breast cancer therapy, usually by intravenous infusion of a solution thereof.
  • the administration of the diphenyl compound to the patient prior to administration of the chemotherapeutic agents is necessary in order to permit the diphenyl compound to inhibit the binding of intracellular histamine in normal and malignant cells and thereby, in effect, shut down the proliferation of the normal cells, but increase proliferation of malignant cells.
  • the length of time prior to administration of the chemotherapeutic agents that the diphenyl compound is administered depends on the diphenyl compound, its mode of administration and the size of the patient. Generally, the diphenyl compound is administered to the patient for about 30 to about 90 minutes, preferably about 60 minutes, prior to administration of the chemotherapeutic agents.
  • the quantity of diphenyl compound administered to the patient depends on the side effects to be ameliorated, but should be at least sufficient to inhibit binding of intracellular histamine in normal cells.
  • the quantity required to achieve the beneficial effects of the present invention depends upon the diphenyl compound employed, the chemotherapeutic agents employed and the quantity of such agents employed.
  • the quantity of diphenyl compound employed in humans is from about 8 to about 320 mg/M 2 of human to which the diphenyl compound is administered, with about 8 and 240 mg/M 2 being the optimal dose for gastro-intestinal and bone marrow protection, respectively.
  • the present invention is able to achieve an enhanced chemotherapeutic effect on breast cancer cells while, at the same time, also protecting normal cells from damage by the chemotherapeutic agents in a wide variety of circumstances where traditional chemotherapy leads to damage of normal cells or tissues not involved in the disease process.
  • the diphenyl compound preferably is used in an amount of about 3 to about 10 mg/kg of patient, administered intravenously over a period of about 30 to about 90 minutes prior to administration of the chemotherapeutic agents and continuing for the period of administration of the chemotherapy agent.
  • a second regimen for DPPE/Taxotere treatment is the intravenous administration of an aqueous solution of DPPE for 80 minutes, with the last 20 minutes being accompanied by infusion of the Taxotere, followed by infusion of Taxotere alone for 40 minutes.
  • the chemotherapy agents which are employed herein preferably are used in a total amount of 75 to about 225 mg/M 2 of patient consistent with the identity of the chemotherapy agent.
  • the chemotherapeutic agents may be administered in an amount of about 50 to about 60 mg/M 2 of patient for doxorubicin or epirubicin, about 175 to about 225 mg/M 2 of Taxol and about 75 to about 100 mg/M 2 of Taxotere.
  • patients with inflammatory breast cancer or T3 to T4 breast cancer are subjected to a number of cycles of chemotherapy at predetermined intervals to reduce the size of the tumor to an operable size.
  • the number of cycles for each patient is generally about 5 to about 8 cycles, with about 21 to about 28 days between each cycle.
  • patients were subjected to 6 cycles at time intervals of 21 days.
  • a Phase II clinical trial was conducted on patients having inflammatory or T3 to T4 breast cancer in which patients were administered DPPE followed by doxorubicin or epirubicin and Taxol or Taxotere.
  • Various data from the clinical trial were collected and analyzed.
  • This Example illustrates the neoadjuvant treatment of inflammatory or T3-T4 breast cancer.
  • DPPE was administered at a dose of 6 mg/M 2 over 80 minutes with a combination of epirubicin or doxorubicin at a dose of 50 mg/M 2 and Taxol at a dose of 175 mg/M 2 or Taxotere at a dose of 75 mg/M 2 over the last 20 minutes and during a further 180 minutes for Taxol or 60 minutes for Taxotere, at a dose of 2.5 mg/kg.
  • the treatment was repeated at 21 day intervals for 6 cycles.
  • the eight patients with inflammatory or T3 to T4 breast cancer had no previous chemo- or radiotherapy. When the chemotherapy cycles were complete, the cancerous tissue was removed and the patients observed.
  • the present invention provides a neoadjuvant chemotherapeutic treatment of inflammatory or T3 to T4 breast cancer.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Prostheses (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Claims (9)

  1. Verwendung von mindestens einer Diphenylverbindung der Formel
    Figure imgb0008
     wobei X und Y jeweils Fluor, Chlor oder Brom sind, Z eine Alkylengruppe aus 1 bis 3 Kohlenstoffatomen oder =C=O ist oder die Phenylgruppen so verbunden sind, dass ein Dreiringsystem gebildet wird, o und p 0 oder 1 sind, R1 und R2 jeweils eine Alkylgruppe sind, die 1 bis 3 Kohlenstoffatome enthält, oder so miteinander verbunden sind, dass ein Heterozyklus mit dem Stickstoffatom gebildet wird, und n 1, 2 oder 3 ist, oder pharmazeutisch annehmbare Salze davon, und der Kombination eines chemotherapeutischen Anthracyclin-Wirkstoffs und eines chemotherapeutischen Taxan-Wirkstoffs bei der Herstellung eines Medikaments zur neoadjuvanten Chemotherapie menschlicher Patienten mit inflammatorischem Brustkrebs oder T3- oder T4-Brustkrebs indem die Patienten einer Mehrzahl von Chemotherapie-Zyklen in zuvor festgelegten Intervallen unterzogen werden bis das Krebsgewebe auf eine operierbare Größe reduziert ist oder sich im Rückzug befindet, wobei jeder Zyklus umfasst:
    (a) zunächst Verabreichen der mindestens einen Diphenylverbindung an den Patienten, und
    (b) gefolgt von ausreichend Zeit, um die Inhibition der Bindung intrazellulären Histamins zu ermöglichen, anschließend Verabreichen der Kombination chemotherapeutischer Wirkstoffe an den Patienten.
  2. Verwendung gemäß Anspruch 1, wobei die Gruppe
    Figure imgb0009
     eine Diethylaminogruppe, eine Dimethylaminogruppe, eine Morpholingruppe oder eine Piperazingruppe ist, vorzugsweise eine Diethylaminogruppe, wobei hier Z -CH2 ist, n 2 ist und o und p jeweils 0 sind, gegebenenfalls in Form eines Hydrochlorid-Salzes.
  3. Verwendung wie in Anspruch 1 oder 2 beansprucht, wobei besagter chemotherapeutischer Anthracyclin-Wirkstoff Doxorubicin oder Epirubicin ist.
  4. Verwendung wie in einem der Ansprüche 1 bis 3 beansprucht, wobei besagter chemotherapeutischer Taxan-Wirkstoff Taxol oder Taxoter ist.
  5. Verwendung wie in einem der Ansprüche 1 bis 4 beansprucht, wobei besagte Diphenylverbindung dem Patienten 30 bis 90 Minuten, vorzugsweise 60 Minuten, vor besagter Verabreichung von besagter Kombination chemotherapeutischer Wirkstoffe verabreicht wird, vorzugsweise durch intravenöse Infusion einer Lösung der Diphenylverbindung über einen Zeitraum von bis zu 90 Minuten vor der Verabreichung besagter chemotherapeutischer Wirkstoffe und während die Verabreichung besagter Kombination chemotherapeutischer Wirkstoffe beibehalten wird, weiter bevorzugt durch Verabreichen besagter Diphenylverbindung für 60 Minuten vor dem Verabreichen besagter Kombinationen chemotherapeutischer Wirkstoffe und wobei besagte Verabreichung während der intravenösen Infusion von besagter Kombination chemotherapeutischer Wirkstoffe beibehalten wird.
  6. Verwendung wie in Anspruch 5 beansprucht, wobei die Verabreichung von chemotherapeutischem Taxan-Wirkstoff, gegebenenfalls in Kombination mit chemotherapeutischem Anthracyclin-Wirkstoff, in 20 Minuten unter Beibehaltung der Infusion der Diphenylverbindung erfolgt, gefolgt von der andauernden Infusion der Diphenylverbindung für den Rest der Verabreichung des chemotherapeutischen Taxan-Wirkstoffs.
  7. Verwendung wie in einem der Ansprüche 1 bis 6 beansprucht, wobei besagte Diphenylverbindung in einer Menge von 8 bis 240 mg/M2 von besagtem Patienten, vorzugsweise von 3 bis 10 mg/kg des Patienten, weiter bevorzugt von 6 mg/kg verabreicht wird.
  8. Verwendung wie in einem der Ansprüche 1 bis 7 beansprucht, wobei besagte Kombination chemotherapeutischer Wirkstoffe in einer Menge von 50 bis 60 mg/M2, vorzugsweise 50 mg/M2 des Patienten für Doxorubicin und Epirubicin, 175 bis 225 mg/M2, vorzugsweise 175 mg/M2 für Taxol und 75 bis 100 mg/M2, vorzugsweise 75 mg/M2 für Taxoter verabreicht werden.
  9. Verwendung wie in einem der Ansprüche 1 bis 8 beansprucht, wobei die Anzahl an Zyklen der chemotherapeutischen Behandlung 5 bis 10 beträgt, die in Intervallen von 21 bis 28 Tagen verabreicht werden.
EP03750185A 2002-09-03 2003-09-02 Präoperative behandlung von brustkrebs Expired - Lifetime EP1545709B1 (de)

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US40724202P 2002-09-03 2002-09-03
US407242P 2002-09-03
PCT/CA2003/001335 WO2004022163A1 (en) 2002-09-03 2003-09-02 Neoadjuvant treatment of breast cancer

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EP1545709A1 EP1545709A1 (de) 2005-06-29
EP1545709B1 true EP1545709B1 (de) 2007-11-14

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US (2) US20060160755A1 (de)
EP (1) EP1545709B1 (de)
JP (1) JP2006516532A (de)
KR (1) KR20060039387A (de)
AT (1) ATE378089T1 (de)
AU (1) AU2003269621A1 (de)
CA (1) CA2497246A1 (de)
DE (1) DE60317537T8 (de)
WO (1) WO2004022163A1 (de)

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GB201121924D0 (en) * 2011-12-20 2012-02-01 Fahy Gurteen Labs Ltd Detection of breast cancer

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US5618846A (en) * 1990-12-17 1997-04-08 University Of Manitoba Treatment method for cancer
US5798339A (en) * 1990-12-17 1998-08-25 University Of Manitoba Treatment method for cancer
US5616846A (en) * 1994-10-27 1997-04-01 Kwasnik; Joseph W. Method and apparatus for current regulation and temperature compensation
JP2005512983A (ja) * 2001-11-01 2005-05-12 ワイエム バイオサイエンシーズ インコーポレイテッド 癌治療におけるｎ，ｎ−ジエチル−２−［−４−（フェニルメチル）−フェノキシ］エタナミンモノハイドロクロライド（ｄｐｐｅ）の使用
JP2005512996A (ja) * 2001-11-09 2005-05-12 ユニヴァーシティ オブ マニトーバ 乳癌の治療

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AU2003269621A1 (en) 2004-03-29
DE60317537T8 (de) 2009-02-05
US20080318880A1 (en) 2008-12-25
DE60317537D1 (de) 2007-12-27
DE60317537T2 (de) 2008-10-23
KR20060039387A (ko) 2006-05-08
CA2497246A1 (en) 2004-03-18
US20060160755A1 (en) 2006-07-20
ATE378089T1 (de) 2007-11-15
JP2006516532A (ja) 2006-07-06
WO2004022163A1 (en) 2004-03-18
EP1545709A1 (de) 2005-06-29

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